The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Surgery, radiation therapy, and chemotherapy have been the standard accepted approaches for treatment of cancers including leukemia, solid tumors, and metastases. Immunotherapy (sometimes called biological therapy, biotherapy, or biological response modifier therapy), which uses the body's immune system, either directly or indirectly, to shrink or eradicate cancer has been studied for many years as an adjunct to conventional cancer therapy. It is believed that the human immune system is an untapped resource for cancer therapy and that effective treatment can be developed once the components of the immune system are properly harnessed. As key immunoregulatory molecules and signals of immunity are identified and prepared as therapeutic reagents, the clinical effectiveness of such reagents can be tested using well-known cancer models. Immunotherapeutic strategies include administration of vaccines, activated cells, antibodies, cytokines, chemokines, as well as small molecular inhibitors, anti-sense oligonucleotides, and gene therapy (Mocellin, et al., Cancer Immunol. & Immunother. (2002) 51: 583-595; Dy, et al., J. Clin. Oncol. (2002) 20: 2881-2894, 2002).
The growth and metastasis of tumors depends to a large extent on their capacity to evade host immune surveillance and overcome host defenses. Most tumors express antigens that can be recognized to a variable extent by the host immune system, but in many cases, the immune response is inadequate. Failure to elicit a strong activation of effector T-cells may result from the weak immunogenicity of tumor antigens or inappropriate or absent expression of co-stimulatory molecules by tumor cells. For most T-cells, proliferation and IL-2 production require a co-stimulatory signal during TCR engagement, otherwise, T-cells may enter a functionally unresponsive state, referred to as clonal anergy.
An important co-stimulatory signal directed through CD28 on T cells occurs via interaction with B7 and its family members including B7.1 (CD80) and B7.2 (CD86) expressed on antigen presenting cells (APC). B7.1, initially discovered as a B-cell antigen, has been shown to induce T cell-dependent rejection of B7-expressing tumors in mice and protect against tumor challenge with parental tumor cells. McHugh et al. 1999, demonstrated proliferation of cytotoxic T-cells in a mixed-lymphocyte-reaction using a recombinant glycol-lipid-anchored protein fused to the extracellular domain of human B7.1.
Previous studies described some success utilizing the B7/CD28 pathway in cancer immunotherapy. Most studies, however, utilized ex vivo genetic modifications of tumor cells to increase the expression of B7 through conventional approaches including transfection or transduction (see e.g., Townsend, et al, Science 259:368-370; Yang, et al., 1995. J. Immunol. 154:2794-2800). Zhou et al., (Cancer Gene Ther. June 2003; 10(6):491-9) described cancer therapeutic effects following administration of vectors encoding B7.1-IgGFc and a separate vector encoding a tumor antigen, CEA.
Singh et al. (2003 Cancer Res. 6:4067-4073) used B7.1-streptavidin after modification of the tumor cell membrane with biotin to rapidly and durably display B7.1 on tumor cells. Other investigators have tried to anchor B7 on the tumor cell membrane by physical methods such as a recombinant glycol-lipid-anchored protein including the extracellular domains of human B7.1 (McHugh, et al., 1995 Proc. Natl. Acad. Sci. 92: 8059-8063). Challita-Eid, et al., (1998 J. Immunol. 160: 3419-3426) described a co-stimulator/antibody fusion protein involving B7.1 fused to an anti-HER2/neu antibody for use in treating tumors. Holliger et al., (Cancer Res. June 1999; 59(12):2909-16) described a B7.1-anti-CEA antibody fusion and its use for immunotherapy of CEA expressing cancers. Gerstmayer et al., (Cancer Immunol Immunother. November-December 1997; 45(3-4):156-8) described a fusion protein of B7-2 and anti-cERB2 for treatment of adenocarcinomas.
T-regulatory cells (“T reg. cells” or “immunoregulatory T cells”) are associated with the CD4+CD25+ phenotype and constitute 5-10% of circulating CD4+ T-cells in humans and rodents. CD4+CD25+ T-reg cells are involved in T cell-mediated immunological self-tolerance. Specifically, in vivo injection of anti-CD25 antibody has been reported to regress leukemia and solid tumors in animal models (Onizuka, 1999). However, in most of these studies, T-reg depletion resulted in either incomplete tumor reduction or only a delay in the growth of well-established tumor implants.
Although much has been learned about controlling and directing an immune response, there is need for newer and more effective immunotherapeutic approaches to cancer therapy.